Development of LRRK2 PROTAC degraders as chemical probes and potential lead compounds for the treatment of Parkinson's disease

帕金森病（PD）是世界范围内第二常见的神经退行性疾病，目前没有治疗方法可以阻止PD的发作和/或进展。富含亮氨酸的重复激酶2（LRRK 2）中的激酶激活G2019 S突变是PD最常见的遗传原因之一，并激发了开发LRRK 2靶向治疗的工作，包括LRRK 2激酶抑制剂。然而，目前的LRRK 2激酶抑制剂，虽然在临床试验中，促进LRRK 2和微管协会，潜在的不良副作用。因此，提出了另一种LRRK 2靶向策略，称为LRRK 2蛋白水解靶向嵌合体（PROTAC）。LRRK 2 PROTAC是异双功能小分子，其由结合LRRK 2的配体组成，通过接头与结合E3泛素连接酶的配体缀合。通过在LRRK 2蛋白附近募集E3泛素连接酶，LRRK 2 PROTAC可以通过泛素-蛋白酶体途径诱导LRRK 2的泛素化和随后的降解。通过设计和合成几组LRRK 2 PROTAC化合物并在多个细胞系上用降解测定筛选它们，我们鉴定了在纳摩尔范围浓度下降解LRRK 2的有效LRRK 2 PROTAC。本研究的目标是通过结构修饰进一步提高这些LRRK 2 PROTAC的效力，并通过详细的体外和体内表征以及PD相关生物学研究将其鉴定为治疗PD的化学探针和潜在先导化合物。

Parkinson's Disease (PD) is the second most common neurodegenerative disorder worldwide and no treatment is currently available to halt the onset and/or progression of PD pharmacologically. The kinase-activating G2019S mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) is one of the most common genetic causes of PD and has motivated work to develop LRRK2-targeted therapies, including LRRK2 kinase inhibitors. However, current LRRK2 kinase inhibitors, albeit in clinical trials, promote LRRK2 and microtubule association, underlying potential undesirable side effects. Alternative LRRK2-targeting strategy, known as LRRK2 Proteolysis Targeting Chimera (PROTAC) is therefore proposed. LRRK2 PROTACs are heterobifunctional small molecules that consist of a ligand that binds LRRK2, conjugated to a ligand that binds an E3 ubiquitin ligase via a linker. By recruiting a E3 ubiquitin ligase in close proximity to a LRRK2 protein, LRRK2 PROTACs can induce the ubiquitination and subsequent degradation of LRRK2 through the ubiquitin-proteasome pathway. By designing and synthesizing a few sets of LRRK2 PROTAC compounds and screening them with degradation assays on multiple cell lines, we identified potent LRRK2 PROTACs that degraded LRRK2 at nanomolar range concentrations. The goal of this fellowship is to further improve the potencies of these LRRK2 PROTACs through structural modification and qualify them as chemical probes and potential lead compounds for the treatment of PD by detailed in vitro and in vivo characterization and PD-related biology studies.